Jung-Jun Min

Evaluation of a Mitochondrial Voltage Sensor, (18F-Fluoropentyl)Triphenylphosphonium Cation, in a Rat Myocardial Infarction Model

Radiolabeled lipophilic cationic compounds, such as 18F-labeled phosphonium salt, accumulate in the mitochondria through a negative inner transmembrane potential. The purpose of this study was to develop and evaluate (18F-fluoropentyl)triphenylphosphonium salt (18F-FPTP) as a myocardial PET agent. Methods: A reference compound of 18F-FPTP was synthesized via 3-step nucleophilic substitution reactions and was radiolabeled via 2-step nucleophilic substitution reactions of no-carrier-added 18F-fluoride. Accumulations of 18F-FPTP, 3H-tetraphenylphosphonium, and 99mTc-sestamibi were compared in a cultured embryonic cardiomyoblast cell line (H9c2). The biodistribution of 18F-FPTP was assessed using BALB/c mice. The 18F-FPTP small-animal PET study was performed in Sprague–Dawley rats with or without left coronary artery (LCA) ligation. Results: 18F-FPTP was synthesized with a radiochemical yield of 15%–20% and radiochemical purity of greater than 98%. Specific activity was greater than 6.3 TBq/μmol. Cell uptake of 18F-FPTP was more than 15-fold higher in H9c2 than in normal fibroblasts (human normal foreskin fibroblasts). Selective collapse of mitochondrial membrane potential substantially decreased cellular uptake for 18F-FPTP and 3H-tetraphenylphosphonium, compared with that for 99mTc-sestamibi. The biodistribution data in mice (n = 24) showed rapid blood clearance and high accumulation in the heart. Heart-to-blood ratios at 10 and 30 min were 54 and 133, respectively. Heart-to-lung and heart-to-liver ratios at 10, 30, and 60 min were 4, 4, and 7 and 4, 5, and 7, respectively. Dynamic small-animal PET for 60 min after injection of 18F-FPTP showed an initial spike of radioactivity, followed by retention in the myocardium and rapid clearance from the background. 18F-FPTP small-animal PET images in LCA-occluded rats demonstrated sharply defined myocardial defects in the corresponding area of the myocardium. The myocardial defect size measured by 18F-FPTP small-animal PET correlated closely with the hypoperfused area measured by quantitative 2,3,5-triphenyltetrazolium chloride staining (r2 = 0.92, P < 0.001). Conclusion: The excellent pharmacokinetics of 18F-FPTP and its correlation with 2,3,5-triphenyltetrazolium chloride staining in normal and LCA-occluded rats suggest that this molecular probe may have a high potential as a mitochondrial voltage sensor for PET. This probe may also allow high throughput, with multiple daily studies and a wide distribution of PET myocardial imaging in the clinic.

Focal pulmonary uptake during Tc-99m myocardial perfusion SPECT imaging.

Purpose To evaluate the incidence and origin of abnormal focal pulmonary uptake during myocardial perfusion SPECT imaging (MSPECT). Methods For evaluation of chest pain, 790 men and 581 women (mean age, 56 ± 13 years) underwent MSPECT. All of them received adenosine for pharmacologic stress and Tc-99m tetrofosmin (TF, n = 817) or Tc-99m sestamibi (MIBI, n = 554) for myocardial perfusion imaging. Results Review of chest radiography with or without computed tomography revealed 111 (8.1%) focal pulmonary diseases. Among them, 38 (34.2%) showed focal pulmonary uptake (TF, 22; MIBI, 16); 27 (30.7%) of 88 showed previous pulmonary tuberculosis; 2 of 10 (20%) benign pulmonary nodules; 4 of 5 (80%) metastatic lung cancers; 2 of 4 (50%) primary lung cancers; and 3 of 4 (75%) pneumonias. No difference in uptake was noted for the two imaging agents. Intensity of uptake did not vary with origin of the uptake. Focal abnormal pulmonary uptake was found in 2.8% of patients undergoing MSPECT and in 34.2% of patients in whom radiological examinations showed regional pulmonary disease. In patients with abnormal pulmonary uptake on MSPECT, 16% had a malignant lesion, whereas 75% of patients with a pulmonary nodule shown on radiography and focal pulmonary uptake on MSPECT had a malignant lesion. Conclusions Although the incidence of abnormal pulmonary uptake during MSPECT was very low, the incidence of malignant lesions in the patients with nodular pulmonary uptake was relatively high.

Dipyridamole modulated Tc-99m sestamibi lung SPECT in small cell lung cancer

PURPOSE In this study, the authors wanted to determine whether dipyridamole-modulated MIBI (dipyridamole-MIBI) could enhance the prediction of the response to chemotherapy in patients with small cell lung cancer. METHODS Twenty-seven patients with biopsy-proved small cell lung cancer (25 men, 2 women; mean age, 61 +/- 7 years) underwent dipyridamole-MIBI SPECT 3 to 7 days before starting chemotherapy (80 mg/m2 etoposide and 80 mg/m2 cisplatin every 3 or 4 weeks for at least two cycles). Tomographic images before and after dipyridamole (0.84 mg/kg) were acquired 1 hour after injection of 370 (10 mCi) and 1,110 (30 mCi) MBq MIBI, respectively. The response to chemotherapy was grouped as specified as complete response (CR), partial (PR), no change (NC), or progressive disease (PD), according to the change in tumor size on chest roentgenography and CT. Patients showing CR and PR were classified as responders, and those who showed NC and PD were considered nonresponders. RESULTS Among the 27 patients, 22 were responders (3 CR, 19 PR) and 5 were nonresponders (3 NC, 2 PD). The tumor-to-normal lung ratio (T:NL) of responders was significantly higher than that of nonresponders. The diagnostic accuracy of the T:NL ratio to differentiate responders and nonresponders was 33.3%, with a cutoff value of 2.5, which was significantly improved to 77.8% when an increased T:NL ratio after dipyridamole was assigned to a nonresponder. Furthermore, all patients with CR showed diminished T:NL ratios after dipyridamole, and all patients with NR showed an increased T:NL ratio after dipyridamole. CONCLUSION Dipyridamole-MIBI SPECT could enhance the prediction of response to chemotherapy in patients with small cell lung cancer.

Tc-99m pyrophosphate uptake in small areas of myocardial injury produced by radiofrequency catheter ablation of arrhythmias

Radiofrequency produces small circumscribed areas of myocardial damage and is now used most commonly for ablation of arrhythmias. The proper position of a catheter can be determined easily by fluoroscopy. However, the degree of tissue destruction cannot be assessed by electronic or radiographic techniques. Seventeen patients with arrhythmia were studied 2 days after radiofrequency catheter ablation of arrhythmias by Tc-99m pyrophosphate scintigraphy. In 14 of the 17 patients (82.4%), myocardial lesions produced by radiofrequency ablation were successfully demonstrated by SPECT imaging, whereas none showed positive uptake on planar images. Two cases are illustrated.